Extended release pharmaceutical formulations with controlled impurity levels

ABSTRACT

The present invention provides extended release pharmaceutical formulations of valsartan with controlled impurity levels. Particularly, the present invention provides extended release valsartan formulation which is substantially free of valsartan R-isomer impurity.

FIELD OF THE INVENTION

The present invention provides extended release pharmaceuticalformulations of valsartan with controlled impurity levels. Particularly,the present invention provides extended release valsartan formulationwhich is substantially free of valsartan R-isomer impurity.

BACKGROUND OF THE INVENTION

Valsartan is a potent, orally active nonpeptide tetrazole derivativethat selectively inhibits angiotensin II receptor type 1. By blockingthe action of angiotensin, valsartan causes reduction in blood pressureand is therefore used in treatment of hypertension, congestive heartfailure and post-myocardial infarction. Valsartan also known as(S)-N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valineor N-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-N-valeryl-L-valine, has thefollowing structure and is marketed as the free acid under the nameDIOVAN.

DIOVAN is prescribed as immediate release oral tablets in dosages of 40mg, 80 mg, 160 mg and 320 mg of valsartan.

The quality and safety of pharmaceuticals can be significantly affectedby the presence of impurities. Consequently, testing and controllinggeneration of impurities in the active pharmaceutical ingredient (API)during synthesis and in the pharmaceutical product during manufacturebecomes imperative. Likewise, the presence of impurities in valsartanformulation may affect its safety and shelf life. USP monograph forvalsartan describes two liquid chromatographic determinations forlimiting a total of three related compounds, valsartan related compoundsA, B and C. Valsartan related compound A having the following structure,is the R-enantiomer of valsartan and is chemically known as(R)-N-valeryl-N-([2′-(1H-tetrazole-5-yl)biphen-4-yl]methyl)-valine. Itis generated by isomerization of valsartan S-isomer and is commonlyreferred to as Impurity A.

Various attempts have been made to control the levels of valsartanR-isomer impurity in valsartan during synthesis and provide anenantiomeric excess of S-valsartan. U.S. Pat. No. 7,728,021 andUS2006/0281891 discuss processes for obtaining valsartan insubstantially pure enantiomeric form. Though attempts have been made toprovide valsartan API with an enantiomeric excess of S-isomer, not manyattempts have been made to control generation of valsartan impurity Aduring the preparation of pharmaceutical formulations. WO2009/135646discusses an immediate release formulation of valsartan wherein fillersuch as solid sugar alcohol consisting of mannitol, xylitol, maltitol,sorbitol, lactitol, erythritol, isomalt and mixtures thereof isemployed. The solid sugar alcohols have been discussed to shorten thewet granulation process because less drying time is needed to achieve aresidual humidity suitable for tabletting and thereby provideformulations with an impurity profile which is better since tablets arefor less time under stressful conditions.

However, attempts have not been made to control the levels of impurity Ain controlled release pharmaceutical formulations of valsartan.

The absolute bioavailability of valsartan is about 25%. Pharmaceuticallyactive agents which exhibit low bioavailability unfortunately create aneed for frequent dosing of a large amount of the active agent in orderto provide and maintain therapeutic levels. The need for frequent dosingpresents patient compliance problems. Attempts have therefore been madeto deliver valsartan in an extended release form. Further, since therelatively low bioavailability of valsartan is primarily due to its poorsolubility in the acid milieu of the stomach, attempts have been made toimprove the bioavailability of valsartan by incorporation ofsolubilizers in the formulations.

WO2009/084040 discusses controlled release once a day formulation ofvalsartan in the form of a gastroretentive dosage form comprisingsolubilized active agent. Such formulations however have been identifiedto have increased levels of impurity A which is not desirable.Incorporation of solubilizers to improve the solubility andbioavailability of valsartan necessitates treating valsartan withsolubilizers by different methods and at different temperature and timeconditions. Such treatments tend to result in the generation of impurityA in the formulations, thereby presenting a need to monitor and controlvalsartan R-isomer impurity when preparing extended releasepharmaceutical formulations, particularly extended release formulationscomprising solubilizers.

The present inventors after rigorous studies provide extended releaseformulations of valsartan which are substantially free of valsartanR-isomer. The present inventors provide extended release formulationscomprising valsartan, at least one solubilizer, at least one releasemodifier and at least one pharmaceutically acceptable excipient; whereinvalsartan is completely or partially solubilized with the solubilizer atcontrolled solubilization conditions to provide formulations which aresubstantially free of valsartan R-isomer.

SUMMARY OF THE INVENTION

The present invention provides extended release pharmaceuticalformulations of valsartan with controlled impurity levels. Particularly,the present invention provides extended release valsartan formulationwhich is substantially free of valsartan R-isomer impurity. The presentinvention further relates to extended release formulations comprisingvalsartan, at least one solubilizer, at least one release modifier andat least one pharmaceutically acceptable excipient; wherein theformulation is substantially free of valsartan R-isomer.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides extended release formulations ofvalsartan which are substantially free of valsartan R-isomer impurity.The term “substantially free” as used herein refers to extended releaseformulations comprising not more than about 1% by weight of thevalsartan R-isomer impurity. In another embodiment, the extended releaseformulations of the present invention comprise not more than about 0.8%by weight of the valsartan R-isomer impurity. In a further embodiment,the extended release formulations of the present invention comprise notmore than about 0.7% by weight of the valsartan R-isomer impurity.

The term “composition” or “formulation” or “dosage form” has beenemployed interchangeably for the purpose of the present invention andmeans that it is a pharmaceutical formulation which is suitable foradministration to a patient. For the purpose of the present invention,the terms “controlled release” or “sustained release” or “extendedrelease” or “modified release” or “prolonged release” have been usedinterchangeably and mean broadly that the active agent is released at apredetermined rate that is different or slower than immediate release ofthe active agent.

In one embodiment, the present invention provides extended releasepharmaceutical formulations comprising valsartan and at least onesolubilizer; wherein the formulation is substantially free of valsartanR-isomer impurity. In a further embodiment, the present inventionprovides extended release pharmaceutical formulations comprisingvalsartan, at least one solubilizer, at least one release modifier andat least one pharmaceutically acceptable excipient; wherein theformulation is substantially free of valsartan R-isomer.

In one embodiment, valsartan employed in the formulations of the presentinvention is in the form of salts, esters, amides, prodrugs, activemetabolites, analogs, and the like. In a further embodiment, valsartanin crystalline, substantially crystalline, amorphous, substantiallyamorphous, dissolved or solubilized form and the like or anycombinations thereof may be employed. In another embodiment, thecrystalline form of valsartan may have different polymorphs. Alldifferent polymorphs, solvates, hydrates, salts of valsartan are withinthe purview of this invention. The term “substantially” referred toherein with respect to the form of the active means not less than 90% ofthe active is present in that active form. In one embodiment, valsartanis present in the formulations of the present invention in asubstantially amorphous faun. In one embodiment, valsartan is employedin the formulations of the present invention in an amount typicallyranging from about 40 mg to about 640 mg. In a further embodiment, theamount of valsartan employed in the formulations of the presentinvention is from about 40 mg to about 320 mg. In another embodiment,the amount of valsartan employed in the formulations of the presentinvention is from about 80 mg to about 320 mg.

In one embodiment, the present invention provides extended releasepharmaceutical formulations comprising valsartan, at least onesolubilizer, and at least one pharmaceutically acceptable excipient;wherein (i) valsartan is completely or partially solubilized using oneor more solubilizers and (ii) the formulation is substantially free ofvalsartan R-isomer. In another embodiment, the present inventionprovides extended release pharmaceutical formulations comprisingvalsartan, at least one solubilizer, at least one release modifier andat least one pharmaceutically acceptable excipient; wherein (i)valsartan is completely or partially solubilized using one or moresolubilizers and (ii) the formulation is substantially free of valsartanR-isomer. In a still further embodiment, the present invention furtherprovides extended release pharmaceutical formulations comprisingvalsartan, at least one solubilizer, at least one release modifier andat least one pharmaceutically acceptable excipient; wherein (i)valsartan is completely or partially solubilized using one or moresolubilizers at controlled solubilization conditions and (ii) theformulation is substantially free of valsartan R-isomer.

In one embodiment, one or more solubilizers employed in the compositionsof the present invention may be polymeric or non-polymeric in nature. Ina further embodiment, one or more solubilizers include, but are notlimited to, cationic, anionic, zwitterionic, nonionic, hydrophilic,hydrophobic or amphiphilic surfactants and the like or any combinationsthereof. The ionic surfactants include, but are not limited to,alkylammonium salts; fusidic acid salts; fatty acid derivatives of aminoacids, oligopeptides, or polypeptides; glyceride derivatives of aminoacids; lecithins or hydrogenated lecithins; Iysolecithins orhydrogenated Iysolecithins; phospholipids or derivatives thereof;Iysophospholipids or derivatives thereof; carnitine fatty acid estersalts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyllactylates; mono- or di-acetylated tartaric acid esters of mono- ordi-glycerides; succinylated mono- or di-glycerides; citric acid estersof mono- or di-glycerides; or mixtures thereof. The amphiphilicsurfactants include, but are not limited to, d-a-tocopheryl polyethyleneglycol 1000 succinate and d-a-tocopherol acid salts such as succinate,acetate, etc. The non-ionic surfactants include, but are not limited to,fatty plcohols; glycerol fatty acid esters; acetylated glycerol fattyacid esters; lower alcohol fatty acid esters; propylene glycol fattyacid esters; sorbitan fatty acid esters; polyethylene glycol sorbitanfatty acid esters; sterols and sterol derivatives; polyoxyethylatedsterols or sterol derivatives; polyethylene glycol alkyl ethers; sugaresters; sugar ethers; lactic acid derivatives of mono- or diglycerides;oil-soluble vitamins/vitamin derivatives; PEG fatty acid esters;polyglycerized fatty acid; polyoxyethylene-polyoxypropylene blockcopolymers; transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols wherein thecommonly used oils are castor oil or hydrogenated castor oil, or anedible vegetable oil such as corn oil, olive oil, peanut oil, palmkernel oil, almond oil and the commonly used polyols include glycerol,propylene glycol, ethylene glycol, polyethylene glycol, sorbitol andpentaerythritol; or mixtures thereof. In another embodiment of thepresent invention, the one or more solubilizers that may be employedinclude polyethylene-polyoxypropylene block copolymer (Lutrol® seriesBASF) and d-a-tocopheryl polyethylene glycol 1000 succinate (Vitamin E25 TPGS® by Eastman) or combinations thereof.

In one embodiment, in the compositions of the present inventionvalsartan and one or more solubilizers may be employed in differentratios. It is contemplated within the scope of the invention that theratio of valsartan to solubilizers may range from about 50:1 to about1:50. In one embodiment, the ratio of valsartan to solubilizers is fromabout 20:1 to about 1:20. In another embodiment, the ratio of valsartanto solubilizer is from about 10:1 to about 1: 10.

In an embodiment, the one or more solubilizers include, but are notlimited to, PEG-20-glyceryl stearate, PEG-40 hydrogenated castor oil,PEG-6 corn oil, lauryl macrogol-32 glyceride, stearoyl macrogolglyceride, polyglyceryl-10 monodioleate, propylene glycol oleate;propylene glycol dioctanoate, propylene glycol caprylate/caprate,glyceryl monooleate, glycerol monolinoleate, glycerol monostearate,PEG-20 sorbitan monolaurate, PEG-4 lauryl ether, sucrose distearate,sucrose monopalmitate, polyoxyethylene-polyoxypropylene block copolymer,polyethylene glycol 660 hydroxystearate, sodium lauryl sulphate, sodiumdodecyl sulphate, propylene glycol alginate, sodium taurocholate, sodiumglycocholate, sodium deoxycholate, betains, polyethylene glycol,d-alpha-tocopheryl polyethylene glycol 1000 succinate, and mixturesthereof.

In a further embodiment, valsartan is treated with one or moresolubilizers. In another embodiment, valsartan is completely orpartially solubilized using one or more solubilizers. In one embodiment,valsartan is completely or partially solubilized using one or moresolubilizers at controlled solubilization conditions. The term“solubilized” as used herein refers to improved or increased solubilityform of valsartan. “Improved or increased solubility form of valsartan”refers to a form of valsartan wherein valsartan is intimately dispersedin at least one solubilizer, and the dissolution of valsartan there fromis not less than about 30% in 0.1N HCl in 30 minutes. In a furtherembodiment, the dissolution of valsartan there from is not less thanabout 50% in 0.1N HCl in 30 minutes. In another embodiment, thedissolution of valsartan there from is not less than about 70% in 0.1NHCl in 30 minutes. The term “completely or partially” as used hereinrefers to whether the entire or part of the valsartan dose issolubilized.

It is contemplated within the scope of the invention that the processesemployed for solubilization of valsartan may include but are not limitedto melt granulation, solvent treatment, wet granulation, physical mixingor spray drying and the like or combinations thereof. In one embodimentvalsartan may be completely or partially solubilized using the meltgranulation method. In the case of melt granulation, the solubilizer ismelted. Valsartan is then added and mixed with the molten mass, andallowed to solidify to prepare granules. In another embodiment thesolubilizers are melted. Valsartan is then added and mixed with themolten mass. This blend is further mixed with diluents, acidulants,disintegrants and the like or mixtures thereof, capable of convertingthis semisolid mass into dry powder. Non limiting examples of diluentsinclude, but are not limited to, celluloses such as microcrystallinecellulose, silicon dioxide, silicates, magnesium aluminum silicate,calcium silicate, and the like or mixtures thereof. Non-limitingexamples of acidulants include, but are not limited to, fumaric acid,citric acid and the like or mixtures thereof. Non-limiting examples ofdisintegrants include, but are not limited to, crospovidone,croscarmellose sodium and the like or mixtures thereof. In anotherillustrative embodiment of this system, valsartan is granulated using amolten solubilizer. In another embodiment, valsartan and the solubilizerboth may be heated together and congealed to room temperature. Inanother embodiment, valsartan may be solubilized using solvent treatmentmethod. In the case of solvent treatment method, either the solubilizeror valsartan or both are dissolved in a solvent which is then removedusing different methods, such as but not limited to, evaporation, spraydrying or the like or combinations thereof. The resultant mass comprisesa blend of valsartan and solubilizer. The solvent employed in thissystem may be aqueous or non-aqueous. In a further embodiment, valsartanmay be solubilized using physical mixing. Valsartan may be intimatelydry-mixed using a low shear granulator, a V-blender, or a high sheargranulator. In a further embodiment, valsartan may be treated with oneor more solubilizer by wet granulation. In another embodiment, valsartanmay be solubilized with one or more solubilizers by spray drying. In oneembodiment, the method of solubilization of valsartan employed is meltgranulation. It is contemplated within the scope of the invention that acombination of aforementioned processes can be employed for treatingvalsartan with solubilizers. It is also contemplated within the scope ofthe invention that any process known in the art suitable for makingpharmaceutical compositions in general may be employed for the purposeof this invention.

Without being bound to any theory it is believed that the process ofsolubilization of valsartan causes the generation of valsartan R-isomerimpurity. Studies involving exposure of valsartan active ingredient tovarying temperatures indicate that valsartan R-isomer impurity is notgenerated when the active as such is exposed to increased temperatures.However, valsartan R-isomer impurity is generated when valsartan isdispersed in or is intimately mixed with at least one solubilizer atcertain temperature ranges for prolonged time periods. In oneembodiment, valsartan R-isomer impurity is generated when valsartan isdispersed in or is intimately mixed with at least one molten solubilizerat specific temperature ranges for certain time periods. It is believedthat valsartan S-isomer when intimately dispersed in at least onesolubilizer at high temperatures of about 75° C. or higher for prolongedtime periods of more than about 15 minutes during the solubilizationprocess gets the necessary medium and energy to undergo isomerization togive the valsartan R-isomer. The exposure of valsartan to hightemperature during the solubilization process could be due to directexposure thereof to thermal energy or conversion of other forms ofenergy to thermal energy. In a further embodiment, it is believed thatsolubilizers provide necessary medium for isomerization, highertemperature provides sufficient energy for conversion of S-isomer intoR-isomer and with prolonged exposure to higher temperature conditionsthe amount of R-isomer impurity generated is further increased.

In one embodiment, the process of solubilizing valsartan is thereforecarried out at controlled time and temperature conditions. Controlledtime and temperature conditions appear not to provide sufficient energynecessary for conversion of valsartan S-isomer to the R-form therebyreducing the generation of the R-impurity and providing extended releasepharmaceutical formulations that are substantially free of the R-isomer.The present invention relates to an extended release pharmaceuticalformulation comprising valsartan which is completely or partiallysolubilized with the solubilizer at controlled solubilizationconditions.

In a further embodiment, the process of solubilization of valsartan iscarried out at a temperature of not more than about 75° C. In anotherembodiment, in the process of solubilization of valsartan withsolubilizer, valsartan may be exposed to temperatures of not more thanabout 75° C. In one embodiment, when the process of solubilization ismelt granulation process, the product bed temperature is maintained atabout 35° C. to about 75° C. In another embodiment, the process ofsolubilization of valsartan is carried out at a temperature of not morethan about 75° C. for a time period of about 15 seconds to about 60minutes. In one embodiment, the process of solubilization of valsartanis carried out at a temperature of not more than about 75° C. for a timeperiod of about 15 seconds to about 30 minutes. In a further embodiment,the process of solubilization of valsartan is carried out at atemperature of not more than about 75° C. for a time period of about 1minute to about 30 minutes. In yet another embodiment, the process ofsolubilization of valsartan is carried out at a temperature of not morethan about 75° C. for a time period of about 5 minutes to about 30minutes. The solubilized valsartan formed with such controlledtemperature and time conditions during melt granulation controls thelevels of impurity A to be within desired limits.

In a further embodiment, release modifiers employed in the extendedrelease formulations of the present invention include, but are notlimited to, polymeric release retardants, non-polymeric releaseretardants or any combinations thereof. In another embodiment, swellingor non-swelling type of release retardants may be employed in thecompositions of the present invention. Release modifiers are employed inthe compositions of the present invention to control the release ofvalsartan and/or solubilized valsartan. Polymeric release modifiersemployed for the purpose of the present invention include, but are notlimited to, cellulose derivatives; cross-linked polyvinyl pyrrolidone,polyhydric alcohols; saccharides, gums and derivatives thereof; vinylderivatives, polymers, copolymers or mixtures thereof; maleic acidcopolymers; polyalkylene oxides or copolymers thereof; acrylic acidpolymers and acrylic acid derivatives; or any combinations thereof.Cellulose derivatives include, but are not limited to, ethyl cellulose,methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose,hydroxypropyl ethylcellulose, carboxymethylethyl cellulose,carboxy-ethylcellulose, carboxymethyl hydroxyethylcellulose,hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methylcellulose, carboxymethyl cellulose (CMC), methylhydroxyethyl cellulose,methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose,sodium carboxymethyl cellulose, or combinations thereof. In oneembodiment, polymeric release retardants of one or more differentviscosities may be employed. In a further embodiment, the releasemodifier employed in the extended release formulations of the presentinvention is hydroxypropyl methyl cellulose. Non-polymeric releasemodifiers employed for the purpose of the present invention include, butare not limited to, fats, oils, waxes, fatty acids, fatty acid esters,long chain monohydric alcohols and their esters or combinations thereof.The amount of release modifier in the dosage form generally varies fromabout 5% to about 90% by weight of the dosage form.

In another embodiment, the pharmaceutically acceptable excipients thatmay be employed in the compositions of the present invention include butare not limited to, acid source, gas generating agents, binders,lubricants, diluents, disintegrants, glidants, colorants, pH modifiers,pore-formers, and the like or mixtures thereof.

In a further embodiment, acidulants may be employed in the compositionsof the present invention. Non-limiting examples of acidulants that maybe employed in the compositions of the present invention includealiphatic or aromatic, saturated or unsaturated, monobasic acid(monocarboxylic acid), dibasic acid (dicarboxylic acid) or tribasic acid(tricarboxylic acid). In one embodiment of the present invention, theacidulant is malic acid, tartaric acid, fumaric acid, maleic acid,aspartic acid or. citric acid and the like or any combinations thereof.The acidulants also function as acid source when with the gas generatingagent as an effervescent couple. In a further embodiment, thepharmaceutical composition of the present invention may comprise atleast one gas generating agent. The gas generating agents also referredto as effervescent agent aid in the formation of highly porous,preferably honeycombed structure and enhances the buoyancy of theformulation. The gas generating agent employed for the purpose of thepresent invention is selected from, but not limited to, alkali andalkaline-earth metal carbonates and bicarbonates such as sodiumbicarbonate, sodium glycine carbonate, potassium bicarbonate, ammoniumbicarbonate, sodium bisulfite, sodium metabisulfite, sodium carbonate,potassium carbonate and the like or combinations thereof. In oneembodiment, the gas generating agent is used at concentration from about0.5 weight % to about 25 weight % of the dosage form.

Non-limiting examples of suitable binders that may be employed in thecompositions of the present invention include, but are not limited to,starch, pregelatinized starch, polyvinyl prrolidone (PVP), copovidone,cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC),hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC) and theirsalts and the like or combinations thereof. Non-limiting examples ofdiluents that may be employed in the compositions of the presentinvention include, but are not limited to, starch, dicalcium phosphate,microcrystalline cellulose, lactose monohydrate, dextrate hydrated andthe like or combinations thereof. Suitable lubricants that may beemployed include, but are not limited to, magnesium stearate, calciumstearate, stearic acid, talc, sodium stearyl fumarate and the like orcombinations thereof. Non-limiting examples of glidants that may beemployed include, but are not limited to, colloidal silica, colloidalsilicon dioxide, silica gel, precipitated silica, and the like orcombinations thereof. Suitable pore forming agents such as, but notlimited to, dextrates, non-GMO dextrates, lactose, sodium chloride, andthe like or combinations may be employed in the formulations of thepresent invention. Suitable adsorbents that may be used in theformulations of the present invention, include but are not limited to,silicates such as aluminum magnesium metasilicate, calcium silicate, andthe like; microcrystalline celluloses and the like or combinationsthereof. Suitable colorants such as, but not limited to, ferric oxide(Sicovit Red 30 E172) may be employed in the compositions of the presentinvention. Disintegrating agents such as, but not limited to, starch,sodium starch glycolate, pregelatinised starch, crosslinked polyvinylpyrrolidone, crosslinked carboxy methylcellulose, or ion exchange resin,may be employed in the composition if required. In one embodiment,disintegrating agents as listed herein above may be employed in thecompositions of the present invention to improve the dissolution.

In a further embodiment, the formulation of the present invention is inthe forth of an extended release formulation. In another embodiment theextended release formulation of the present invention is in the form ofa gastroretentive dosage form. For the purpose of the present inventionthe term “gastroretentive” or “gastric retention” or “gastroretention”or “retained in upper gastrointestinal tract” when used with respect tothe dosage forth of the present invention, means that the dosage form orat least a portion thereof remains in the upper gastrointestinal tractincluding stomach, for about 30 minutes or more. In another embodiment,the gastroretentive dosage form of the present invention remains in theupper gastrointestinal tract including stomach, for about 30 minutes toabout 12 hours. In another embodiment controlled release formulation ofthe present invention is in the form of a gastroretentive dosage form.In a further embodiment, gastroretentive dosage farms that are retainedin the upper gastrointestinal tract for a prolonged period of time afteroral administration and release the active ingredient continuously at apredetermined rate or in a sustained manner are employed for deliveringvalsartan.

In one embodiment, the gastroretentive extended release formulation ofthe present invention further in addition to valsartan, at least onesolubilizer, at least one release modifier and at least onepharmaceutically acceptable excipient, further comprises at least oneswelling agent, and at least one swelling enhancer.

In one embodiment, the swelling polymers employed in the dry state or ina form that has substantial capacity for water uptake may be employed inthe compositions of the present invention. Non-limiting examples of suchswelling polymers employed in the present invention include, but are notlimited to, polyalkylene oxides; cellulosic polymers; acrylic acid andmethacrylic acid polymers, and esters thereof, maleic anhydridepolymers; polymaleic acid; poly(acrylamides); poly(olefinic alcohol)s;poly(N-vinyl lactams); polyols; polyoxyethylated saccharides;polyoxazolines; polyvinylamines; polyvinylacetates; polyimines; starchand starch-based polymers; polyurethane hydrogels; chitosan,polysaccharide gums; aglinates; zein; shellac-based polymers;polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose,calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid,maltodextrin, pre-gelatinized starch and polyvinyl alcohol, and the likeor mixtures thereof. In a further embodiment one or more swellingpolymers employed for the purpose of the present invention include, butare not limited to, polyethylene oxide, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, methyl cellulose,polyacrylic acid, maltodextrin, pre-gelatinized starch, polyvinylalcohol and the like or mixtures thereof. In another embodiment, theweight percent of the swelling polymer in the final compressed dosageform is about 5 to about 95 weight percent.

In one embodiment, the swelling enhancers that may be employed in thecomposition of the present invention include, but are not limited to,low-substituted hydroxypropyl cellulose, microcrystalline cellulose,cross-linked sodium or calcium carboxymethyl cellulose, cellulose fiber,cross-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid,cross-linked Amberlite resin, alginates, colloidal magnesium-aluminumsilicate, corn starch granules, rice starch granules, potato starchgranules, pregelatinised starch, sodium carboxymethyl starch and thelike or combinations thereof. In another embodiment, the content of theswelling enhancer that may be employed is about 5 to about 90 weightpercent of the formulation. At concentration above about 5% w/w thenon-limiting list of agents listed above function as swelling enhancersand help swelling polymers to swell rapidly.

In a further embodiment, the gastroretentive dosage form of the presentinvention may be in the form of a monolithic system, an expandingbilayered or multilayered or in-lay system for oral administration whichis adapted to deliver the drug at a predetermined rate. In oneembodiment, valsartan is incorporated in monolithic matrix type ofextended release gastroretentive formulation. In another embodiment,valsartan is incorporated in a bilayered gastroretentive dosage formthat consists of a drug layer and a gastroretentive expanding layerwherein the drug is released at a predetermined rate from the druglayer. In a further embodiment pharmaceutical controlled releasegastroretentive composition in the form of an expanding bilayered systemfor oral administration is provided to deliver valsartan from a firstlayer immediately upon reaching the gastrointestinal tract, and todeliver same or different active, from a second layer, in a sustainedmanner over a specific time period. The second layer is also adapted toprovide expanding nature for the dosage system, thereby making thedosage system have greater retention in the stomach.

In yet another illustrative embodiment according to the invention, theextended release formulation with improved bioavailability may beoptionally coated. Surface coatings may be employed for aestheticpurposes or for dimensionally stabilizing the dosage form. The coatingmay be carried out using any conventional technique employingconventional ingredient. A surface coating can, for example, be obtainedusing a quick-dissolving film using conventional polymers such as, butnot limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose,carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol,polymethacrylates or the like or combinations thereof. Tablets of thepresent invention may vary in shape including, but not limited to, oval,triangle, almond, peanut, parallelogram, pentagonal. It is contemplatedwithin the scope of the invention that the dosage form can beencapsulated. Tablets in accordance with the present invention may bemanufactured using conventional techniques of common tableting methodsknown in the art such as direct compression, dry granulation, wetgranulation and extrusion melt granulation.

Further, in one embodiment, the present invention provides a process ofpreparing an extended release formulation comprising: preparingsolubilized valsartan by solubilization using with one or moresolubilizer; blending said solubilized valsartan with at least onerelease modifier, and at least one pharmaceutically acceptableexcipient; lubricating the blend to form a lubricated blend; compressingthe blend to form a monolithic tablet. In another embodiment, thepresent invention provides a process of preparing an extended releasegastroretentive formulation comprising: preparing solubilized valsartanby solubilization using one or more solubilizers; blending saidsolubilized valsartan with at least one release modifier, at least oneswelling polymer and at least one pharmaceutically acceptable excipient;lubricating the blend to form a lubricated blend; compressing the blendto form a monolithic tablet. Furthermore, the present invention alsoprovides a process of preparing an extended release gastroretentivedosage form of valsartan comprising: preparing solubilized valsartan bysolubilization using one or more solubilizers; blending said solubilizedvalsartan with at least one release modifier and at least onepharmaceutically acceptable excipient, lubricating the blend to formdrug layer blend; blending at least one swelling polymer, at least onepharmaceutically acceptable excipient, lubricating the blend to form agastroretentive layer blend; and compressing the drug layer and thegastroretentive layer to form a bilayer tablet. In one embodiment, theextended compositions of the present invention are in the form ofbilayered gastroretentive dosage form comprising the active layer andthe gastroretentive layer. In a further embodiment, the extended releaseformulation of the present invention is prepared by (i) melting thesolubilizer, (ii) adding valsartan to the molten solubilizer, (iii)intimately dispersing valsartan with molten solubilizer at controlledsolubilization conditions, (iv) adding diluents to the molten mass andmixing, (v) cooling the granules formed, (vi) blending with at least onerelease modifier and at least one pharmaceutically acceptable excipientwith the granules (vii) lubricating the blend to faint an active layerblend (viii) blending and granulating part of at least one swellingpolymer, at least one swelling enhancer and at least onepharmaceutically acceptable excipient; (ix) blending the granules withremaining amounts of at least one swelling polymer, at least oneswelling enhancer and at least one pharmaceutically acceptable excipient(x) lubricating the blend to form the gastroretentive layer blend (ix)compressing the drug layer blend and gastroretentive layer blend to formbilayered gastroretentive tablet dosage farm.

In one embodiment, the solubilized valsartan is prepared undercontrolled solubilization conditions as discussed hereinbefore. In afurther embodiment, the solubilized valsartan is prepared at atemperature of not more than about 75° C. as discussed hereinbefore.

In another embodiment, levels of impurity A studied for six months at40° C./75% RH for the solubilized valsartan prepared by melt granulationat controlled temperature conditions as stated above indicated thatimpurity A levels are within the desired limits. In a furtherembodiment, the pharmaceutical compositions of the present invention aresubjected to stability studies for 6 months at different temperaturesand relative humidity (RH) conditions such as 25° C./60% RH, 40° C./75%RH and were found to be stable with controlled levels of impurity A.

In one embodiment, the extended release gastroretentive formulation ofthe present invention that may be coated or uncoated, single layered ormultilayered dosage form gradually swells upon contact with the gastricfluid. The time taken for swelling may vary from about 15 minutes toabout 4 hours. In a further embodiment, the time taken for swelling iswithin about 15 minutes to about 3 hours. In another embodiment, thetime taken for swelling is within about 15 minutes to about 2 hours. Twodimensions of the dosage form namely length and width expand to morethan about 8 mm after swelling within about 2 hours in media simulatingtypical gastric environment (0.1 N hydrochloric acid). In oneembodiment, the length and width of the dosage form expand to more thanabout 10 mm after swelling within about 2 hours in media simulatingtypical gastric environment (0.1 N hydrochloric acid). In anotherembodiment, the length and width of the dosage form expand to more thanabout 12 mm after swelling within about 2 hours in media simulatingtypical gastric environment (0.1 N hydrochloric acid).

The extended release formulations according to the present inventionallow for controlled release of valsartan. In one embodiment thevalsartan is released over a period of more than about 4 hours. In afurther embodiment the valsartan is released over a period of about 6hours. In one embodiment the valsartan is released over a period ofabout 8 hours. In another embodiment the valsartan released over aperiod of about 12 hours. In another embodiment the valsartan releasedover a period of about 24 hours. In one embodiment, not more than about40% vaslartan is released from the extended release formulations of thepresent invention in 1 hour and not less than 75% valsartan is releasedover 8 hours. Further, within the purview of the present invention, areincluded formulations that comprise a combination of valsartan withother drugs or active agents which may be delivered in an immediaterelease or modified release manner. In a further embodiment, theextended release pharmaceutical compositions of the present inventionproduce therapeutically desirable pharmacokinetic profiles in humansubjects.

In one embodiment, the extended release formulations of the presentinvention exhibit pH dependent release of valsartan. In one embodiment,the release of valsartan from a 160 mg dosage form (Example 4) in 0.1 NHCl is not more than about 20% in thirty (30) minutes, not more thanabout 40% in one (1) hour, and about 60% in four (4) hours to abouteight (8) hours.

In one embodiment, the extended release formulations of the presentinvention exhibit pH dependent release of valsartan. In one embodiment,the release of valsartan from a 160 mg dosage form (Example 4) in 0.001N HCl is not more than about 20% in thirty (30) minutes, not more thanabout 40% in one (1) hour, and about 80% in four (4) hours to abouteight (8) hours.

In one embodiment, the extended release formulations of the presentinvention exhibit pH dependent release of valsartan. In one embodiment,the release of valsartan from a 160 mg dosage form (Example 4) in 0.1 Macetate buffer (about pH 4.5) is not more than about 20% in thirty (30)minutes, not more than about 40% in one (1) hour, and about 100% in four(4) hours to about eight (8) hours.

In one embodiment, the extended release formulations of the presentinvention exhibit pH dependent release of valsartan. In one embodiment,the release of valsartan from a 160 mg dosage form (Example 4) in 0.05 MTris buffer (about pH 6.8) is not more than about 20% in thirty (30)minutes, not more than about 40% in one (1) hour, and about 100% in four(4) hours to about eight (8) hours.

In one embodiment, the extended release formulations of the presentinvention may be combined with other anti-hypertensive agents. Theadditional anti-hypertensive agent may be delivered in immediate orextended release manner. In a further embodiment is provided the use ofextended release pharmaceutical composition of valsartan of the presentinvention, which is substantially free of valsartan R-isomer impurity,for the manufacture of a medicament for treatment of hypertension andheart failure. In one embodiment, the present invention provides amethod for treatment of hypertension and heart failure comprisingadministering to the subject in need thereof extended releasepharmaceutical compositions of valsartan of the present invention, whichis substantially free of valsartan R-isomer impurity. In anotherembodiment, the present invention provides a method for reducing therisk of fatal and nonfatal cardiovascular events, primarily strokes andmyocardial infarctions, comprising administering to the subject in needthereof extended release pharmaceutical compositions of valsartan of thepresent invention, which is substantially free of valsartan R-isomerimpurity.

While the invention has been described with reference to exemplaryembodiments, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings without departing from the essential scopethereof. Therefore, it is intended that the invention not be limited tothe particular embodiment disclosed as the best mode contemplated forcarrying out this invention, but that the invention will include allembodiments falling within the scope of the appended claims.

The invention is further illustrated by the following examples, whichare for illustrative purposes and should not be construed as limitingthe scope of the invention in any way.

EXAMPLES Example 1 Compatibility Study for Valsartan Related Compound A(Valsartan R-Isomer Impurity)

Valsartan and valsartan solubilized in molten solubilizers as depictedin tables I and II respectively were subjected to compatibility studiesat the following condition:

-   -   2 weeks 60° C. closed glass vial

TABLE I Sr. No. Ingredients Quantity/vial (mg) 1. Valsartan 1000

TABLE II Sr. Ratio No API and Excpients Drug:Excipients 1.Valsartan:Kolliphor P 407 1:0.5 2. Valsartan:Kolliphor TPGS 1:0.5 3.Valsartan:Kolliphor P 407:Kolliphor TPGS 1:0.5:0.5

Solubilized valsartan used for the study was prepared by melting thesolubiliser/s (Kolliphor P 407, Kolliphor TPGS and combination thereof)in a beaker at water bath temperature 65° C. The drug was mixed with themolten solubiliser/s uniformly at water bath temperature 65° C. and thecooled mass was used in the studies.

Levels of Impurity A were evaluated at the tabulated conditions asmentioned in Table III.

TABLE III 2 Weeks 60° C. Impurity Initial Closed glass Vial ValsartanAPI 0.03 0.05 Valsartan and Kolliphor P 407 0.05 1.94 Valsartan andKolliphor TPGS 0.04 2.2 Valsartan and Kolliphor TPGS + 0.26 2.38Kolliphor P 407

This study indicated the following:

-   -   A) Valsartan R-isomer impurity (Impurity A) was not generated in        valsartan API sample at the different conditions evaluated.    -   B) Valsartan R-isomer impurity (Impurity A) was generated in the        valsartan and solubilizer/s samples. Increased levels of        impurity A was found to be generated in the samples maintained        at 60° C. for 2 weeks.

The above study indicates that impurity A is generated in samplescomprising valsartan and solubilizers, when they are maintained athigher temperature condition for prolonged time period, while thevalsartan API sample does not indicate such a generation and increase inthe levels of valsartan impurity A.

Example 2 Evaluation of Impact of Solubilization Temperature on ImpurityA Levels

TABLE IV Composition of solubilized valsartan Ingredients mg/tabletValsartan 160 Vitamin E Polyethylene Glycol Succinate (Kolliphor ® 80TPGS) Poloxamer (Kolliphor ® P 407) 80

Procedure:

Three sets of solubilized valsartan were prepared using the aboveexcipients by maintaining the product bed at different temperatures.

-   -   1. Valsartan is added to molten poloxamer and Vitamin E        polyethylene glycol succinate in a jacketed mixer and mixed well        for 15 minutes.    -   2. The product bed temperature is maintained at 60° C. for set        I, at 70° C. for set II and at 80° C. for set III of solubilized        valsartan.

Three sets of granules prepared at different temperature as depictedabove were analyzed for impurity A levels.

TABLE V 3075-153-160 3053-113-160 3024-105-160 (Set I (Set II (Set IIIProcess solubilized solubilized solubilized Parameters active) active)active) Product Temp (° C.) 60 70 80 Impurity A 0.02 0.13 0.82

The above study indicates that valsartan related compound A impurity inthe solubilized valsartan increases at higher processing temperature.When product bed temperature is about 80° C., higher amount of impurityA is generated in the solubilized valsartan prepared.

Example 3 Composition of Valsartan Extended Release Tablets 160 mg

TABLE VI Ingredients mg/tablet Active layer Valsartan 160 Vitamin Epolyethylene glycol 80 succinate Poloxamer 80 Microcrystalline Cellulose135 Hydroxypropyl methylcellulose 110 Calcium Silicate 120 Crospovidone35 Fumaric Acid 78 Dextrates 60 Colloidal Silicon Dioxide 10 MagnesiumStearate 20 Ferric Oxide 2 Gastroretentive layer Polyethylene oxide 119Hydroxypropyl methyl cellulose 119 Hydroxyethyl Cellulose 59Crospovidone 120 Microcrystalline Cellulose 29 Polyvinylpyrrolidone 331-vinyl-2-pyrrolidone and vinyl 13 acetate copolymer Sodium Bicarbonate33 Anhydrous Citric Acid 10 Magnesium Stearate 5 Isopropyl Alcohol q.s.Purified Water# q.s. Weight of core tablet 1430 Film coating 60 Totalweight of coated tablet 1490

Procedure:

A) Valsartan is added to molten poloxamer and Vitamin E polyethyleneglycol succinate in a low shear mixer and mixed well for about 15minutes. The product temperature is maintained at 65° C.±10° C.Microcrystalline cellulose, calcium silicate, fumaric acid andcrospovidone are added to above mass and mixed further to get ahomogeneous blend. All other ingredients are added to above mass andgranulated. The granules were dried and lubricated with magnesiumstearate to form active layer blend.

B) Povidone was dissolved in IPA: water mixture with overhead stirring.Polyethylene oxide, hydroxyl propyl methyl cellulose, hydroxyethylcellulose, crospovidone, and microcrystalline cellulose were passedthrough the sieve and dry mixed in rapid mixer. The binder solution wasadded to the dry mix and the mass was granulated and subsequently driedin a fluidized bed dryer to get desired loss on drying. Sized driedgranules were blended with other excipients like lactose,microcrystalline cellulose, sodium bicarbonate and citric acid and thenlubricated using magnesium stearate to form gastroretentive layer blend.

A bilayer gastroretentive tablet of valsartan was prepared bycompressing the drug layer blend and the gastroretentive layer blend.The bilayered tablets were subsequently film coated.

Analysis: The granules of part A above were analyzed by HPLC forImpurity A levels and the results are as mentioned in the below table:

TABLE VI (A) Impurity Initial impurity levels in granules ValsartanImpurity A 0.15% Total impurities 0.04%

These granules of valsartan prepared under controlled solubilizationconditions were found to have controlled levels of impurity A.

The tablets prepared under controlled solubilization conditions asmentioned above were subjected to stability studies for 6 months at 40°C./75% relative humidity (RH) and then analyzed by HPLC for impurity Alevels. The tablets prepared under controlled solubilization conditionswere found to be stable with controlled levels of impurity A.

TABLE VII Storage Pack conditions Details Impurity Initial 3 M 6 M 40°C./ 120 cc HDPE Valsartan 0.11% 0.20% 0.36% 75% RH bottle with ImpurityA 38 mm CRC Total 0.03% 0.15% 0.24% (30's count) Impurities

Example 4 Coated Extended Release Formulations of Valsartan (160 mg doseand 320 mg Dose)

Two embodiments of coated extended release formulations of valsartanhaving 160 mg and 320 mg respectively are depicted in Tables VIII andTable IX. Table VIII describes compositions of valsartan core tablets.One of the procedures suitable for preparing such core tablets has beenpresented in Example 3. Table IX describes compositions of the dualcoating system. One of the procedures suitable for preparing suchcoating system has been presented in Example 4. The amount ofingredients listed in the Tables VI, VIII, and IX are for the purpose ofdemonstration and are not intended to limiting. The precise amount ofeach ingredient depicted in the Examples and Tables can be adjustedbased on needs and requirements.

TABLE VIII Compositions of valsartan core tablets (160 mg and 320 mgvalsartan) Ingredients mg/unit mg/unit Active layer Valsartan 160 320Vitamin E polyethylene glycol succinate 80 160 Poloxamer 80 160Microcrystalline Cellulose 135 270 Hydroxypropyl methylcellulose 110 220Calcium Silicate 120 240 Crospovidone 35 70 Fumaric Acid 78 156Dextrates 60 120 Colloidal Silicon Dioxide 10 20 Magnesium Stearate 2040 Ferric Oxide 2 4 Gastroretentive layer Polyethylene Oxide 119 238Hydroxypropyl methyl cellulose 119 238 Hydroxyethyl Cellulose 59 118Crospovidone 120 240 Microcrystalline Cellulose 29 38Polyvinylpyrrolidone 33 66 1-vinyl-2-pyrrolidone and vinyl acetate 13 26copolymer Sodium Bicarbonate 33 66 Anhydrous Citric Acid 10 20 MagnesiumStearate 5 10 Isopropyl Alcohol q.s. q.s. Purified Water^(#) q.s. q.s.Total 1430 2860

TABLE IX Compositions of the dual coating systems Ingredients mg/unitmg/unit Valsartan core tablets 1430 2860 Seal coating Opadry Clear03K19229 15.00 30.00 Isopropyl alcohol^(#) q.s. q.s. Purified water^(#)q.s. q.s. Film coating Polyvinyl Alcohol-based Opadry 200 Blue 45.0090.00 200F105000 Purified water^(#) q.s. q.s. Excipients (imprintingmaterial) Opacode Black S-1-17823 0.104 0.208 Isopropyl alcohol^(#) q.s.q.s. Total 1490 2980

1-29. (canceled)
 30. An extended release pharmaceutical formulation,comprising: a gastroretentive core comprising (a) a therapeuticallyeffective amount of valsartan of about 160 mg; (b1) alpha tocopherolpolyethylene glycol succinate in an amount of about 80 mg; (b2)polyoxyethylene polyoxypropylene block copolymer in an amount of about80 mg; (c) hydroxypropyl methylcellulose in an amount of not less thanabout 200 mg; a dual coating system surrounding the gastroretentivecore; wherein the formulation comprises not more than about 0.7% byweight of valsartan R-isomer impurity; wherein a process ofsolubilization of valsartan is carried out at a temperature between 60°and 70° C.; wherein valsartan is completely or partially solubilizedwith (b1) and (b2); and wherein the dual coating system comprises a sealcoating layer contacting the gastroretentive core.
 31. The extendedrelease formulation of claim 30, wherein the gastroretentive corefurther comprises: (d) microcrystalline cellulose in an amount of about160 mg.
 32. The extended release formulation of claim 30, whereinvalsartan is in crystalline form, substantially crystalline form,amorphous form, substantially amorphous form, or any mixtures thereof.33. The extended release formulation of claim 30, wherein valsartan isin substantially amorphous form.
 34. The extended release formulation ofclaim 30, wherein the formulation comprises not more than about 0.7% byweight of valsartan R-isomer impurity at 40° C./75% RH for 6 months. 35.The extended release formulation of claim 30, wherein the formulationfurther comprises at least one release modifier.
 36. The extendedrelease formulation of claim 30, wherein the formulation furthercomprises at least one pharmaceutically acceptable excipient.
 37. Theextended release formulation of claim 35, wherein the at least onerelease modifier is selected from the group consisting of a polymericrelease modifier, a non-polymeric release modifier, or any combinationthereof.
 38. The extended release formulation of claim 37, wherein thepolymeric release modifier is selected from the group consisting of acellulose derivative; a polyhydric alcohol; a saccharide; a gum orderivative thereof; a vinyl derivative; a polymer, copolymer, or mixturethereof; a maleic acid copolymer; a polyalkylene oxide or copolymerthereof; an acrylic acid polymer or derivative thereof; or anycombinations thereof.
 39. The extended release formulation of claim 37,wherein the non-polymeric release modifier is selected from the groupconsisting of a fat, an oil, a wax, a fatty acid, a fatty acid ester, along chain monohydric alcohol or ester thereof, or any combinationsthereof.
 40. The extended release formulation of claim 36, wherein theat least one pharmaceutically acceptable excipient is selected from thegroup consisting of an acid source, a gas generating agent, a binder, alubricant, a diluent, a disintegrant, a glidant, a colorant, a pHmodifier, a pore-former, and the like, or any combinations thereof.